INHIBITORS OF CYCLIN DEPENDENT KINASE 7 (CDK7)
The present invention provides, inter alia, compounds having the structures of formulas described herein; pharmaceutically acceptable salts, solvates, hydrates, tautomers, and isotopic forms thereof; and compositions (e.g., pharmaceutical compositions and kits) containing one or more of the foregoing. Also provided are methods of administering and uses involving the compounds and/or pharmaceutical compositions for treating or preventing disease. The disease can be a proliferative disease, such as a cancer (e.g., a blood cancer (e.g., a leukemia or lymphoma), a brain cancer, a breast cancer, melanoma, multiple myeloma, or an ovarian cancer) a benign neoplasm, pathologic angiogenesis, or a fibrotic disease. While no aspect of the invention is limited by the biological events that may transpire, administering a compound or other composition described herein may selectively inhibit the aberrant expression or activity of cyclin-dependent kinase 7 (CDK7) and, thereby, induce cellular apoptosis and/or inhibit the transcription of disease-related genes in the patient (or in a biological sample).
1 . A pharmaceutical composition, wherein the composition is formulated for oral administration and comprises a pharmaceutically acceptable excipient and a compound of Formula (I):
or a pharmaceutically acceptable salt, stereoisomer, or isotopic form thereof, wherein:
ring A is
ring B is
wherein each of R 2 , R 3 , R 4 and R 5 are, independently, hydrogen or —CH 3 ;
X and Y are, independently, N or CH;
R 1 is hydrogen or fluoro; and
the compound is other than:
2 . The pharmaceutical composition of claim 1 , wherein ring A is
3 .- 4 . (canceled)
5 . The pharmaceutical composition of claim 1 , wherein ring B is
6 .- 7 . (canceled)
8 . The pharmaceutical composition of claim 1 , wherein ring A is
and ring B is
9 . The pharmaceutical composition of claim 1 , wherein X is CH and Y is CH.
10 . The pharmaceutical composition of claim 1 , wherein X is N.
11 . A pharmaceutical composition, wherein the composition is formulated for oral administration and comprises a pharmaceutically acceptable excipient and a compound of Formula II:
or a pharmaceutically acceptable salt, stereoisomer, or isotopic form thereof, wherein:
ring A is
and
R 1 is hydrogen or fluoro.
12 . The pharmaceutical composition of claim 1 , wherein the compound of Formula (I) is selected from the group consisting of:
or a pharmaceutically acceptable salt, stereoisomer, or isotopic form thereof.
13 . A pharmaceutical composition, wherein the composition is formulated for oral administration and comprises a pharmaceutically acceptable excipient and a compound selected from the group consisting of:
or a pharmaceutically acceptable salt, stereoisomer, or isotopic form thereof.
14 . (canceled)
15 . A method of treating a patient suffering from a disease associated with aberrant activity of CDK7, wherein the disease is a proliferative disease, an infectious disease, or a disease caused by or associated with expanded repeats of simple nucleotide tracts, and the method comprises a step of administering to the patient a therapeutically effective amount of the pharmaceutical composition of claim 1 .
16 .- 17 . (canceled)
18 . The method of claim 15 , wherein the proliferative disease is a cancer or benign neoplasm.
19 . The method of claim 18 , wherein the cancer is a blood cancer, a bone cancer, a brain cancer, a breast cancer, a colorectal cancer, a lung cancer, a melanoma, a neuroblastoma, an ovarian cancer, or a pancreatic cancer.
20 . The method of claim 19 , wherein the blood cancer is chronic lymphocytic leukemia (CLL), chronic myelomonocytic leukemia (CMML), acute lymphoblastic leukemia (ALL), T-cell acute lymphoblastic leukemia (T-ALL), chronic myelogenous leukemia (CML), lymphoma, or multiple myeloma.
21 .- 25 . (canceled)
26 . The method of claim 19 , wherein the blood cancer is acute myelogenous leukemia (AML).
27 . The method of claim 19 , wherein the bone cancer is osteosarcoma or Ewing's sarcoma.
28 . The method of claim 19 , wherein the breast cancer is triple-negative breast cancer (TNBC).
29 . The method of claim 19 , wherein the cancer is a brain cancer.
30 . The method of claim 19 , wherein the lung cancer is small cell lung cancer (SCLC).
31 . The method of claim 19 , wherein the cancer is a colorectal cancer, a melanoma, a neuroblastoma, an ovarian cancer, or a pancreatic cancer.
32 . The method of claim 15 , wherein the method further comprises a step of administering, to the patient, a therapeutically effective amount of an anti-proliferative agent, an anti-cancer agent, an immunosuppressant agent, or a pain-relieving agent.